This briefing describes the regulated use of the technology for the indication specified, in the setting described, and with any other specific equipment referred to. It is the responsibility of healthcare professionals to check the regulatory status of any intended use of the technology in other indications and settings.
Myriad Genetic Laboratories received CE marking for the specimen collection set for Prolaris on 27 March 2015 and for the entire test (all processes, consumables, equipment and software) on 30 November 2015. In Europe, Prolaris is regulated as an in vitro diagnostic medical device (within the scope of Directive 98/79/EC).
Prolaris is an in vitro diagnostic test which measures gene expression levels in RNA extracted from formalin-fixed, paraffin-embedded (FFPE) prostate tumour samples, taken from needle biopsies or prostatectomy specimens. The test measures the expression levels of 31 cell cycle genes (involved in cell division and duplication) and 15 control or reference genes (those involved in the normal functioning of the cell; Cuzick et al. 2011). From this information, it generates a Prolaris score (also known as the cell cycle progression or CCP score), which is designed to predict either the patient's 10-year risk of mortality using prostate biopsy samples or the 10-year risk of biochemical recurrence using prostatectomy specimens.
FFPE samples (either blocks or slides) are prepared in the local hospital laboratory using the Prolaris specimen collection kit and are sent to the Myriad Genetics laboratory in Germany for processing. Each collection kit is intended for the shipment of specimen(s) for 1 patient only. A Prolaris test request form with the patient's clinical and tumour pathology information must be sent to the laboratory with the sample. One or more samples can be sent per patient. Where multiple samples are sent, a pathologist at Myriad will select the most appropriate sample according to a predefined process. The total turnaround time for the Prolaris results, from the date the sample is shipped to Myriad's laboratory until the report is sent back to the referring clinician (by secure email), is 14 days.
The company provides comprehensive and detailed instructions for sample preparation including the shipment of haematoxylin and eosin-stained slides to aid sample processing.
Previously, the Prolaris score was reported on a scale of −3 to +7, but this has recently been changed to a scale from 0 to 10. In both systems, a higher score indicates a more aggressive cancer and each 1‑unit increase in the score represents a doubling in risk.
The Prolaris test report includes both the Prolaris score and a D'Amico risk analysis, which shows how the patient's score compares to that of patients within the same D'Amico risk category (low or intermediate; the test is not intended for high-risk prostate cancer). This allows differentiation between patients with the same D'Amico risk profiles and, consequently, refinement of level of risk.
According to the new Prolaris scoring system, for patients in the D'Amico low risk category, a Prolaris score below 2.7 indicates that the cancer is less aggressive than the average cancer in this risk category. A Prolaris score above 3.7 indicates a more aggressive cancer. Similarly, for the D'Amico intermediate risk category, Prolaris scores below 3.0 and above 4.0 indicate that the cancer is less aggressive and more aggressive respectively than the average cancer in this risk category.
This analysis is based on Prolaris test results from a population in the US, which may limit its generalisability to the UK.
In clinical practice, the Prolaris score is designed to be used in combination with other clinical and pathological information obtained as part of the normal diagnostic pathway. For example:
The patient's 10-year prostate cancer-specific mortality risk may be estimated based on the combined Prolaris score (from biopsy samples) and CAPRA score (combining the PSA level, Gleason score, patient age, percentage of positive biopsy cores and clinical tumour stage). This mortality risk is also known as the combined clinical-cell-cycle-risk (CCR) score.
The patient's 10-year biochemical recurrence risk may be estimated based on the combined Prolaris score (from prostatectomy specimens) and CAPRA-S score (combining the PSA level before surgery, Gleason score, patient information and tumour characteristics including lymph node involvement).
Prolaris is intended for use in people with low or intermediate-risk localised prostate cancer who have not had hormonal therapy or radiation therapy before biopsy or surgery. Prolaris is not intended for use in people with high-risk prostate cancer.
Prolaris is intended for use in secondary care settings. The test is requested by either oncologists or urologists, who complete a Prolaris test request form and send it to their local pathology department. The samples are prepared by medical laboratory assistants and sent to the Myriad Genetics laboratory in a pre-paid shipping package provided by the manufacturer. No additional specialist training on sample preparation is needed for staff in the pathology department.
The manufacturer recommends that the Prolaris results be used in addition to other clinical and pathological information that is obtained as part of the normal diagnostic pathway.
NICE's guideline on prostate cancer: diagnosis and treatment recommends the use of PSA testing, Gleason score and tumour stage to predict low, intermediate, or high risk of tumour growth and spread, which is in line with the D'Amico risk classifications. The guideline also states that clinicians can use nomograms as a decision support tool to help predict tumour progression and risk of treatment failure. Although the guideline does not recommend specific nomograms, a number of them are readily accessible online including:
Memorial Sloan Kettering Cancer Center (MSKCC) calculator (USA; Memorial Sloan Kettering Cancer Center 2016)
the European prostate risk indicator (SWOP-PRI; Europe; Kranse et al. 2008)
North American Prostate Cancer Prevention Trial Risk Calculator (PCPT-CRC; USA; Thompson et al. 2006).
These nomograms were validated in different populations and require different types of clinical data.
NICE is aware of the following CE-marked test that appears to fulfil a similar function to Prolaris:
Oncotype DX Prostate (Genomic Health).
The list price for Prolaris is £1,800 per test, excluding VAT. Because the samples are processed remotely, each test kit is for 1 patient sample and includes a test request form (including patient, clinical and pathological information), instructions for use, specimen and shipping containers, and pre-paid shipping envelopes. One or more samples can be included per test request. Where multiple samples are sent, a pathologist at Myriad will select the most appropriate sample for testing. There is no increase in costs for this additional step. No charge is made for samples that are not tested (for example, due to insufficient tumour sample or incorrect tumour type). The requesting hospital or clinic will receive an invoice for the test after the Myriad Genetics laboratory has generated a result. No additional equipment needs to be purchased and therefore no maintenance or training is needed.
Online nomograms including those listed above are all free of charge.
Prolaris would be used to help make decisions about treatment for low or intermediate-risk localised prostate cancer in people who are being considered for active surveillance or radical treatment, to estimate the risk of mortality before surgery or the risk of biochemical recurrence after prostatectomy. It would be used in addition to existing risk stratification information.
In terms of current care pathways for prostate cancer, 1 specialist commentator noted that multiple clinical parameters have been investigated as methods of predicting the risk of prostate cancer. Nomograms have also been developed for this purpose. The commentator observed that nomograms could be used as decision support tools to help predict tumour progression and risk of treatment failure, but they suggested that nomograms have shortcomings despite being effective and available for free. Another commentator agreed that nomograms have limitations that make it difficult to use them to accurately predict the risk of prostate cancer, comorbidity or general life expectancy. The commentator stated that nomograms are rarely used in UK practice. The same commentator noted that in patients with low or intermediate risk prostate cancer, tumours may be missed because of their small size. Problems accessing the tumour may arise in some patients with larger tumours that are in front of, above or very close to the prostate apex. In addition, the commentator highlighted that small tumours can be difficult to grade, leading to a significant number of cancers being staged incorrectly compared with results from histology or biopsy. The specialist commentator noted that current measures to improve the accuracy of grading include functional MRI scans before biopsy, systematic biopsies (where multiple biopsies are taken from different regions of the prostate), template biopsies (where 50 to 60 needle biopsies are taken through a grid template with holes spaced 5 mm apart to thoroughly sample the entire prostate) and targeted biopsies guided by MRI.
All 4 specialist commentators identified potential benefits from using Prolaris. One noted that the test could be used to estimate mortality and inform treatment for low or intermediate-risk localised prostate cancer without requiring changes in the organisation, delivery of current services or additional facilities or technology. The same commentator referred to an economic evaluation conducted in the US, which found that using the CCP (Prolaris) score over 10 years reduced patient costs by approximately £1,938 (Crawford et al. 2015). However, a different commentator cautioned that non-UK cost studies cannot be generalised to the NHS. Another commentator anticipated that Prolaris may be helpful before treatment to reduce anxiety in lower-risk patients who are recommended for active surveillance but might prefer active intervention. A third commentator considered that Prolaris was a promising test in an area where no others are available for routine diagnostic use but noted that more evidence was needed. The fourth specialist commentator stated that the rationale for using Prolaris to differentiate between patients with the same D'Amico risk profile is very good and that the link shown between the Prolaris score, biochemical recurrence and cancer-related mortality is clinically relevant and indicates that the test has practical use. The commentator added that Prolaris could be a useful addition to daily practice for guiding shared decision-making. The commentator felt it would be useful to gauge what the uptake of Prolaris would be in the UK, suggesting that a questionnaire to urologists may clarify this. The same commentator felt that a treatment decision change of 47.8% (taken from the Shore et al.  study) was impressive, but was unsure how this would transfer to general prostate cancer clinics. The commentator also noted that clinician preference is a large factor in treatment decisions and that an objective test such as Prolaris would help provide standardisation.
In terms of the limitations of the Prolaris test, 2 commentators noted that the test was expensive considering the current financial burden on the NHS, with 1 commentator stating that it would be very challenging to show that Prolaris is cost effective in the NHS. The second commentator noted that the use of Prolaris, involving preparation and shipping, leads to considerable extra work for clinicians. A third commentator agreed that some pathology laboratories may not have the resources for this extra work and, in these cases, additional funding will be needed. One commentator referred to the Cuzick et al. (2012) study and noted that patients with lower grade prostate cancer had CCP scores greater than 2, so the score was not predictive of the outcome in this clinical subgroup. The commentator speculated whether this would place doubt on the utility of Prolaris in a low-risk population for deciding on immediate or deferred treatment.
All 4 specialist commentators mentioned evidence limitations for Prolaris. One commentator suggested that the strength of evidence was low to moderate and would benefit from additional studies. Three commentators highlighted that the retrospective nature of most of the studies limited their value. One commentator suggested the best evidence would be derived from a large-scale prospective randomised UK radiotherapy trial. Another commentator noted that although there were a relatively low number of studies, the overall cohort size across the studies was good. Overlapping cohorts and the lack of power calculations were also noted as potential limitations by 1 commentator.
Two specialist commentators mentioned that new imaging techniques such as multiparametric MRI (MPMRI) have the potential to identify the most aggressive areas of prostate cancer and allow targeted biopsies or template biopsies for molecular determinants of biologic aggressiveness. One of these commentators suggested that with limited funding and the lack of MPMRI facilities in UK hospitals, money may be better spent on this technology rather than Prolaris. The other commentator suggested that other molecular tests are emerging (based on general features of malignancy such as proliferation indices, or on more specific features for prostate cancer), making it a challenge to predict which would have the best comparative clinical relevance and cost effectiveness. They suggested that head-to-head comparisons across multiple patient cohorts with specifically designed clinically relevant end points should be done.
NICE is committed to promoting equality, eliminating unlawful discrimination and fostering good relationships between people with particular characteristics and others. In producing guidance, NICE aims to comply fully with all legal obligations to:
promote race and disability equality and equality of opportunity between men and women
eliminate unlawful discrimination on grounds of race, disability, age, sex, gender reassignment, marriage and civil partnership, pregnancy and maternity (including women post-delivery), sexual orientation, and religion or belief (these are protected characteristics under the Equality Act 2010).
Black people of African or Caribbean family origin and people aged over 50 years have a higher risk of prostate cancer (Cancer Research UK 2014b). Gender, race and age are protected characteristics as defined in the Equality Act 2010.